Systemic inflammation impairs myelopoiesis and interferon type I responses in humans
Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163<sup>+</sup>SLC39A8<sup>+</sup>CALR<sup>+</sup> monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.
Authors
- Inge Grondman (ORCID: https://orcid.org/0000-0002-4687-9845)
- Guus P. Leijte (ORCID: https://orcid.org/0000-0002-5750-1434)
- Farid Keramati (ORCID: https://orcid.org/0000-0002-3034-4133)
- Walter JFM van der Velden
- Peter Pickkers (ORCID: https://orcid.org/0000-0002-1104-4303)
- Mihai Gheorghe Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
- Ehsan Habibi (ORCID: https://orcid.org/0000-0002-7208-7999)
- Wout Megchelenbrink (ORCID: https://orcid.org/0000-0002-2895-3511)
- Hendrik G. Stunnenberg (ORCID: https://orcid.org/0000-0002-0066-1576)
- Jelle Gerretsen (ORCID: https://orcid.org/0000-0002-8935-7350)
- Manita Bremmers
- Kiki Tesselaar (ORCID: https://orcid.org/0000-0002-9847-0814)
- Niklas Bruse (ORCID: https://orcid.org/0000-0001-5146-5295)
- Matthijs Kox (ORCID: https://orcid.org/0000-0001-6537-6971)
- Selma van Staveren (ORCID: https://orcid.org/0000-0002-2531-209X)
- Annemieke M. Peters van Ton (ORCID: https://orcid.org/0000-0001-7979-5149)
- Cristian Ruiz-Moreno (ORCID: https://orcid.org/0000-0001-9689-7964)
- Erinke van Grinsven (ORCID: https://orcid.org/0000-0001-7743-194X)
- Hidde Heesakkers (ORCID: https://orcid.org/0000-0002-6330-7208)
- Frank Preijers (ORCID: https://orcid.org/0000-0002-7394-7364)
- Brigit M. te Pas (ORCID: https://orcid.org/0000-0002-2777-2540)
- Raoul van de Loop
Institutions
- Broad Institute (US)
- Radboud University Nijmegen (NL)
- University of Ottawa (CA)
- University of Campania "Luigi Vanvitelli" (IT)
- Radboud University Medical Center (NL)
- University of Medicine and Pharmacy of Craiova (RO)
- University Medical Center Utrecht (NL)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Princess Máxima Center (NL)
- Stoas University of Applied Sciences (NL)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-04-18
- DOI
- https://doi.org/10.1038/s41590-025-02136-4
- Citations
- 13
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 10.37
Funders
- ZonMw
- Horizon 2020 Framework Programme